Therapeutic peptides are a successful drug class with attributes that often include high potency, good efficacy and low toxicity. There are over 60 peptide drugs licensed for clinical use worldwide. The market for synthetic peptides has grown from $5 billion in 2004 to currently over $13 billion [1]. According to market research, the number of peptides in clinical development is over 100 and in pre-clinical development is over 400 [2]. The growing success of peptide therapeutics is accentuated by poor stability, low and variable oral bioavailability, rapid plasma clearance and high manufacturing cost relative to conventional small molecules. These limitations often leave industry with no option other than to formulate the peptides in injectable dosage forms, which generates significant manufacturing costs. Reformulation of a peptide into an oral dosage form could reduce the costs associated with sterile manufacture of injectables. However, this depends on the amount of bioactive peptide that is required in the oral dosage form, with concommitant influence upon both the efficiency of the delivery system and the cost to synthesise the therapeutic peptide.
The financial limitations of oral delivery of therapeutic peptides relates to the molecular weight of the peptide in addition to its potency, structural complexity and the frequency of administration. For specialist drug delivery, candidate peptides are carefully selected for reformulation. For example, selecting a complex high molecular weight peptide or protein manufactured by an expensive recombinant approach that subsequently requires repeat daily administration is less likely to be commercially viable in an oral format; given the likelihood that the peptide will have low oral bioavailability. Hence, these financials impediments need to be addressed when choosing the candidate peptides.
In an oral format, insulin for example could be administered earlier in the progression of the diabetes disease. The requirement for needles can, in some cases, reduce patient compliance especially those undergoing treatment for chronic, non-life threatening diseases. Hence, an oral format may improve compliance. From a therapeutic perspective, oral delivery of some peptides can represent a more physiological route compared with injectable formats; since injectable routes can expose diabetics to hyperinsulinemic hypoglycemia [4]. This issues are also imperative for consideration during development of oral delivery systems.
Delivery of a peptide by the oral route could also reduce primary healthcare costs by eliminating the need for skilled professionals to administer certain dosage forms. Improved patient compliance also reduces the requirement for primary intervention. The benefits of delivery by the oral route clearly outweighs delivery by the parenteral route, which is reflected in the fact that two thirds of all pharmaceutical dosage forms are oral products [5].
In recently years, a number of oral peptide dosage forms that are based on both novel and established concepts in oral drug delivery have progressed to clinical assessment with varying levels of success. Significant R&D effort has led to a number of oral insulin formulations reaching clinical trial assessment. To date no oral insulin formulation has been licensed for use in the treatment of diabetes. The most advanced oral peptide formulations in clinical development are solid dosage formulations consisting of conventional admixed solids used in the preparation of enteric coated tablets. Despite such a plethora of research, there are few disclosures that address the mode of dose delivery and design for oral insulin, and hence development issues related to development of solid dosage forms are yet to be addressed.
The main peptides in clinical development include glucagon like peptide-1 (GLP-1), insulin and exenatide, salmon calcitonin (sCT), octreotide, parathyroid hormone (PTH), and human growth hormone (hGH) as well as the polysaccharide drug, low molecular weight heparin (LMWH). In the majority of cases, oral peptide formats in clinical development are new formulations of established parenteral therapeutics, and so the success of the oral format does not relate to the drug efficacy specifically; it will, however, it depends on the performance of the new drug delivery system.
The amount of peptide in many of the oral dosage forms is significantly higher relative to those delivered by the parenteral route which is made feasible by more efficient processes for peptide synthesis. Some of the companies developing oral formulations are also publishing patents to improve efficiency of manufacturing (e.g. Biocon, India U.S. Pat. No. 8,058,391). The higher quantity of active in an oral peptide format permits a certain loss of peptide as it negotiates each of the pre-systemic barriers to the circulation. It is clear that the value of peptide bioavailability becomes less important relative to the achievement of safe, efficient reproducibility. This point is further highlighted by the licensed peptide desmopressin (DDVMP, Ferring, Switzerland), one of only two peptides licensed for delivery by the oral route in a formulation with bioavailability of only 0.1%.
From a biopharmaceutics aspect, the key challenges encountered in oral peptide delivery are pre-systemic degradation, poor permeability across the intestinal epithelium and hepatic metabolism. Peptides are susceptible to chemical instability, conformational instability and enzymatic degradation during manufacture processes such as extrusion, pressing or drying, product storage and subsequent absorption and systemic degradation. The bioactivity of a peptide is very quickly lost in the stomach milieu as the harsh acidic condition can reduce tertiary and quaternary disulphide bridges and can also facilitate hydrolysis of intact peptides into shorter inactive sequences. The gastric environment can be avoided by enteric coating with weakly acidic polymer films that delay release by melting above their pKa in a pH dependant fashion.
Drug solubility is however fundamental in oral peptide delivery and significant research has attempted to improve peptide solubility to address this need. The structure activity function of most peptide drugs and their target receptors make it difficult to reduce the number of amino acids that contribute to the amount of hydrogen bond donors in the molecule or the molecular weight or the Log P; not without very substantial structure activity relationship studies. Approaches have included increasing the molecular weight by alkylation via hydrolysable bonds, and while this increases the Log P, it also increases molecular weight.
Hence, the importance of a suitable dosage form capable of facilitating oral peptide delivery is imperative. Despite the concentration of peptide in the dosage form, inadequate protection from degradation or a lack of permeation enhancement of the peptide across the intestinal epithelium will result in failure in both pre-clinical and clinical development.
A significant volume of research has focused on efforts to improve peptide stability and permeation by chemical modification or non-covalent complexation. Structural modification, including the formation of prodrugs, is a successful drug delivery approach that is commonly used to improve the physicochemical properties of drugs, including peptides and proteins. PEGylation, the conjugation of protein with polymers of polyethylene glycol, is a useful way of increasing serum half-life of biotech drugs that are delivered by the parenteral route.
Synthesis of all peptide with D-amino acids can prevent peptide digestion and improve peptide bioavailability. For example, the substitution of two D-amino acids (alanine and leucine) in the pentapeptide enkephalin improved oral bioavailability by over 20-fold when delivered with amistatin orally in rats. In 2005, Biocon acquired Nobex Corp. (USA) and with it the intellectual property for a PEGylated and alkylated oral insulin format called IN-105 (U.S. Pat. No. 5,359,030 U.S. Pat. No. 5,681,811A, U.S. Pat. No. 6,770,625B2, EP1430082B1 U.S. Pat. No. 6,309,633 B1). Insulin is covalently modified at position B29 with polyethylene glycol using an acyl chain linker, which improves stability of the peptide to proteolysis and reduces mutagenicity without significantly altering the peptides pharmacological activity.
Physical complexation of peptide to a carrier substance is a possible alternative to chemical modification that can improve the lipophilic characteristics of the peptide and in some cases improve the stability of the peptide. Ionic complexation is widely applicable in the formulation of conventional small molecule drugs, to such an extent that it is estimated that 50% of all drugs are formulated as salts.
Furthermore, research also aims to overcome poor efficiency and proteolysis of insulin-B12 conjugates (1:1) has resulted in the evaluation of insulin loaded, B12 coated nanostructures (Access Pharmaceutical, USA) that protect the peptide from degradation and improve the efficiency of permeation. Another example of this strategic approach involves conjugation of target peptide to modified transferrin leading to more favourable pharmacokinetics (U.S. Pat. No. 8,129,504). However, concerns remain in relation to saturable receptors that can reproducibly improve peptide permeation especially when a wide and varied diet is factored into the study design.
It is an object of the invention to overcome at least one of the above-referenced problems.